Methods for think-aloud interviews in health-related resource-use research: the PECUNIA RUM instrument.

BACKGROUND: The think-aloud (TA) approach is a qualitative research method that allows for gaining insight into thoughts and cognitive processes. It can be used to incorporate a respondent's perspective when developing resource-use measurement (RUM) instruments. Currently, the application of TA methods in RUM research is limited, and so is the guidance on how to use them. Transparent publication of TA methods for RUM in health economics studies, which is the aim of this paper, can contribute to reducing the aforementioned gap. METHODS: Methods for conducting TA interviews were iteratively developed by a multi-national working group of health economists and additional qualitative research expertise was sought. TA interviews were conducted in four countries to support this process. A ten-step process was outlined in three parts: Part A 'before the interview' (including translation, recruitment, training), Part B 'during the interview' (including setting, opening, completing the instrument, open-ended questions, closing), and part C 'after the interview' (including transcription and data analysis, trustworthiness). CONCLUSIONS: This manuscript describes the step-by-step approach for conducting multi-national TA interviews with potential respondents of the PECUNIA RUM instrument. It increases the methodological transparency in RUM development and reduces the knowledge gap of using qualitative research methods in health economics.

The healthcare system costs of hip fracture care in South Africa.

Despite rapidly ageing populations, data on healthcare costs associated with hip fracture in Sub-Saharan Africa are limited. We estimated high direct medical costs for managing hip fracture within the public healthcare system in SA. These findings should support policy decisions on budgeting and planning of hip fracture services. PURPOSE: We estimated direct healthcare costs of hip fracture (HF) management in the South African (SA) public healthcare system. METHODS: We conducted a micro-costing study to estimate costs per patient treated for HF in five regional public sector hospitals in KwaZulu-Natal (KZN), SA. Two hundred consecutive, consenting patients presenting with a fragility HF were prospectively enrolled. Resources used including staff time, consumables, laboratory investigations, radiographs, operating theatre time, surgical implants, medicines, and inpatient days were collected from presentation to discharge. Counts of resources used were multiplied by unit costs, estimated from the KZN Department of Health hospital fees manual 2019/2020, in local currency (South African Rand, ZAR), and converted to 2020 US$ prices. Generalized linear models estimated total covariate-adjusted costs and cost predictors. RESULTS: The mean unadjusted cost for HF management was US$6935 (95% CI; US$6401-7620) [ZAR114,179 (95% CI; ZAR105,468-125,335)]. The major cost driver was orthopaedics/surgical ward costs US$5904 (95% CI; 5408-6535), contributing to 85% of total cost. The covariate-adjusted cost for HF management was US$6922 (95% CI; US$6743-7118) [ZAR113,976 (95% CI; ZAR111,031-117,197)]. After covariate adjustment, total costs were higher in patients operated under general anaesthesia [US$7251 (95% CI; US$6506-7901)] compared to surgery under spinal anaesthesia US$6880 (95% CI; US$6685-7092) and no surgery US$7032 (95% CI; US$6454-7651). CONCLUSION: Healthcare costs following a HF are high relative to the gross domestic product per capita and per capita spending on health in SA. As the population ages, this significant economic burden to the health system will increase.

Modelling the lifetime cost-effectiveness of radical prostatectomy, radiotherapy and active monitoring for men with clinically localised prostate cancer from median 10-year outcomes in the ProtecT randomised trial.

BACKGROUND: Optimal management strategies for clinically localised prostate cancer are debated. Using median 10-year data from the largest randomised controlled trial to date (ProtecT), the lifetime cost-effectiveness of three major treatments (radical radiotherapy, radical prostatectomy and active monitoring) was explored according to age and risk subgroups. METHODS: A decision-analytic (Markov) model was developed and informed by clinical input. The economic evaluation adopted a UK NHS perspective and the outcome was cost per Quality-Adjusted Life Year (QALY) gained (reported in UK£), estimated using EQ-5D-3L. RESULTS: Costs and QALYs extrapolated over the lifetime were mostly similar between the three randomised strategies and their subgroups, but with some important differences. Across all analyses, active monitoring was associated with higher costs, probably associated with higher rates of metastatic disease and changes to radical treatments. When comparing the value of the strategies (QALY gains and costs) in monetary terms, for both low-risk prostate cancer subgroups, radiotherapy generated the greatest net monetary benefit (£293,446 [95% CI £282,811 to £299,451] by D'Amico and £292,736 [95% CI £284,074 to £297,719] by Grade group 1). However, the sensitivity analysis highlighted uncertainty in the finding when stratified by Grade group, as radiotherapy had 53% probability of cost-effectiveness and prostatectomy had 43%. In intermediate/high risk groups, using D'Amico and Grade group > = 2, prostatectomy generated the greatest net monetary benefit (£275,977 [95% CI £258,630 to £285,474] by D'Amico and £271,933 [95% CI £237,864 to £287,784] by Grade group). This finding was supported by the sensitivity analysis. Prostatectomy had the greatest net benefit (£290,487 [95% CI £280,781 to £296,281]) for men younger than 65 and radical radiotherapy (£201,311 [95% CI £195,161 to £205,049]) for men older than 65, but sensitivity analysis showed considerable uncertainty in both findings. CONCLUSION: Over the lifetime, extrapolating from the ProtecT trial, radical radiotherapy and prostatectomy appeared to be cost-effective for low risk prostate cancer, and radical prostatectomy for intermediate/high risk prostate cancer, but there was uncertainty in some estimates. Longer ProtecT trial follow-up is required to reduce uncertainty in the model. TRIAL REGISTRATION: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).

Cost-Effectiveness of Caries Prevention in Practice: A Randomized Controlled Trial.

A 2-arm parallel-group randomized controlled trial measured the cost-effectiveness of caries prevention in caries-free children aged 2 to 3 y attending general practice. The setting was 22 dental practices in Northern Ireland. Participants were centrally randomized into intervention (22,600 ppm fluoride varnish, toothbrush, a 50-mL tube of 1,450 ppm fluoride toothpaste, and standardized prevention advice) and control (advice only), both provided at 6-monthly intervals during a 3-y follow-up. The primary outcome measure was conversion from caries-free to caries-active states assessed by calibrated and blinded examiners; secondary outcome measures included decayed, missing, or filled teeth surfaces (dmfs); pain; and extraction. Cumulative costs were related to each of the trial's outcomes in a series of incremental cost effectiveness ratios (ICERs). Sensitivity analyses examined the impact of using dentist's time as measured by observation rather than that reported by the dentist. The costs of applying topical fluoride were also estimated assuming the work was undertaken by dental nurses or hygienists rather than dentists. A total of 1,248 children (624 randomized to each group) were recruited, and 1,096 (549 in the intervention group and 547 in the control group) were included in the final analyses. The mean difference in direct health care costs between groups was £107.53 (£155.74 intervention, £48.21 control, P < 0.05) per child. When all health care costs were compared, the intervention group's mean cost was £212.56 more than the control group (£987.53 intervention, £774.97 control, P < 0.05). Statistically significant differences in outcomes were only detected with respect to carious surfaces. The mean cost per carious surface avoided was estimated at £251 (95% confidence interval, £454.39-£79.52). Sensitivity analyses did not materially affect the study's findings. This trial raises concerns about the cost-effectiveness of a fluoride-based intervention delivered at the practice level in the context of a state-funded dental service (EudraCT No: 2009-010725-39; ISRCTN: ISRCTN36180119).

Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men: study protocol for a randomised controlled trial.

BACKGROUND: Lower urinary tract symptoms (LUTS) comprise storage symptoms, voiding symptoms and post-voiding symptoms. Prevalence and severity of LUTS increase with age and the progressive increase in the aged population group has emphasised the importance to our society of appropriate and effective management of male LUTS. Identification of causal mechanisms is needed to optimise treatment and uroflowmetry is the simplest non-invasive test of voiding function. Invasive urodynamics can evaluate storage function and voiding function; however, there is currently insufficient evidence to support urodynamics becoming part of routine practice in the clinical evaluation of male LUTS. DESIGN: A 2-arm trial, set in urology departments of at least 26 National Health Service (NHS) hospitals in the United Kingdom (UK), randomising men with bothersome LUTS for whom surgeons would consider offering surgery, between a care pathway based on urodynamic tests with invasive multichannel cystometry and a care pathway based on non-invasive routine tests. The aim of the trial is to determine whether a care pathway not including invasive urodynamics is no worse for men in terms of symptom outcome than one in which it is included, at 18 months after randomisation. This primary clinical outcome will be measured with the International Prostate Symptom Score (IPSS). We will also establish whether inclusion of invasive urodynamics reduces rates of bladder outlet surgery as a main secondary outcome. DISCUSSION: The general population has an increased life-expectancy and, as men get older, their prostates enlarge and potentially cause benign prostatic obstruction (BPO) which often requires surgery. Furthermore, voiding symptoms become increasingly prevalent, some of which may not be due to BPO. Therefore, as the population ages, more operations will be considered to relieve BPO, some of which may not actually be appropriate. Hence, there is sustained interest in the diagnostic pathway and this trial could improve the chances of an accurate diagnosis and reduce overall numbers of surgical interventions for BPO in the NHS. The morbidity, and therapy costs, of testing must be weighed against the cost saving of surgery reduction. TRIAL REGISTRATION: Controlled-trials.com - ISRCTN56164274 (confirmed registration: 8 April 2014).

Design and preliminary recruitment results of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).

BACKGROUND: Screening for prostate cancer continues to generate controversy because of concerns about over-diagnosis and unnecessary treatment. We describe the rationale, design and recruitment of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) trial, a UK-wide cluster randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. METHODS: Seven hundred and eighty-five general practitioner (GP) practices in England and Wales were randomised to a population-based PSA testing or standard care and then approached for consent to participate. In the intervention arm, men aged 50-69 years were invited to undergo PSA testing, and those diagnosed with localised prostate cancer were invited into a treatment trial. Control arm practices undertook standard UK management. All men were flagged with the Health and Social Care Information Centre for deaths and cancer registrations. The primary outcome is prostate cancer mortality at a median 10-year-follow-up. RESULTS: Among randomised practices, 271 (68%) in the intervention arm (198,114 men) and 302 (78%) in the control arm (221,929 men) consented to participate, meeting pre-specified power requirements. There was little evidence of differences between trial arms in measured baseline characteristics of the consenting GP practices (or men within those practices). CONCLUSIONS: The CAP trial successfully met its recruitment targets and will make an important contribution to international understanding of PSA-based prostate cancer screening.

Alendronate: an update of its use in osteoporosis.

UNLABELLED: Alendronate (alendronic acid) is a nitrogen-containing bisphosphonate which binds to bone surfaces and inhibits bone resorption by osteoclasts. Oral alendronate 5 or 10 mg/day produces sustained increases in bone mineral density (BMD) in postmenopausal women with or without osteoporosis, in men with primary osteoporosis and in both men and women with or without osteoporosis receiving systemic corticosteroid therapy. Histomorphometric analyses have found that alendronate does not appear to impair bone quality. Alendronate reduced the risk of radiographic vertebral fracture, clinical vertebral fracture or hip fracture by 47 to 56% in postmenopausal women who had > or = 1 existing vertebral fracture and in those with no existing vertebral fractures but who had osteoporosis. In a number of comparative trials in postmenopausal women with osteoporosis, alendronate 10 mg/day was found to be more effective at inducing sustained increases in BMD than intranasal calcitonin, and at least as effective as conjugated estrogens and raloxifene. Alendronate 70 mg administered once weekly and 35 mg twice weekly are as effective at increasing BMD as 10 mg/day in this patient group. In clinical trials, alendronate was generally well tolerated when taken as recommended. Adverse events tended to be transient and associated with the upper GI tract, most commonly including abdominal pain, nausea, dyspepsia, acid regurgitation and musculoskeletal pain. No statistically significant differences between alendronate 10 mg/day and placebo have been found in the incidence of upper GI adverse events in large clinical trials. However, postmarketing surveillance reported a low incidence of adverse events related to the oesophagus. Specific instructions aimed at reducing the risk of upper GI adverse events have been provided by the manufacturer. CONCLUSIONS: Alendronate is effective and generally well tolerated in the treatment of women or men with primary (including postmenopausal) or corticosteroid-induced osteoporosis and in the prevention of osteoporosis in postmenopausal women. The drug has been associated with upper GI tract adverse events, although the extent to which alendronate is responsible for these events has not been clearly established. Alendronate should be considered a treatment of choice in postmenopausal women with osteoporosis. Alendronate is also a suitable treatment option for primary osteoporosis in men and for corticosteroid-induced osteoporosis in both men and women.

Maternal employment and the initiation of breastfeeding.

UNLABELLED: This study examines whether planning to be employed postpartum has an effect on initiation of breastfeeding. Data were collected from questionnaires completed by mothers who were subjects in the prospective, population-based, Avon Longitudinal Study of Pregnancy and Childhood. The mothers of 10,530 full-term singleton infants gave information during pregnancy on their postpartum employment plans and their initial infant feeding methods. Information was also given by 7642 of these mothers on the timing of their postpartum employment plans. Adjusted logistic regression was performed to identify associations between (a) "any" plans to work postpartum and the initiation of breastfeeding, and (b) the timing of the commencement of work postpartum, and the initiation of breastfeeding. A total of 8316 (79%) of the women initiated breastfeeding. The decision to breastfeed was not associated with "any" plans to work postpartum. However, women who planned to commence work prior to 6 wk postpartum were significantly less likely to initiate breastfeeding compared with those not intending to work postpartum. Older, more highly educated women, women who had or were planning to attend childbirth classes, women who were breastfed as infants, women who did not smoke and women who were giving birth to their first child were significantly more likely to initiate breastfeeding. CONCLUSION: Planning to return to employment prior to 6 wk postpartum reduces the likelihood of initiating breastfeeding. As increasing numbers of mothers are returning to work shortly after the birth of their child, this finding could have implications for maintaining the current level of breastfeeding.

Onychomycosis: improved cure rates with itraconazole and terbinafine.

Onychomycosis is a disease that is important to our patients. Based on the current literature, recent developments of newer antifungal agents have improved cure rates of onychomycosis in the past few years (Table 3). No significant differences in safety and tolerability between itraconazole and terbinafine exist. Terbinafine does appear to have a preferable drug interaction profile. Daily therapy with either agent at standard doses has been shown to be effective when compared with placebo. When studies have directly compared daily administration of terbinafine and itraconazole, both medications have shown similar efficacy. Daily terbinafine therapy, however, appears to be more effective than pulse therapy with itraconazole. In addition, one small study showed a trend in favor of continuous rather than intermittent terbinafine therapy and similar efficacy of intermittent itraconazole and intermittent terbinafine therapy. Furthermore, terbinafine is more cost-effective than itraconazole. Finally, as quality-of-life data suggest, onychomycosis is important to our patients and affects both physical and psychosocial components of our patients' lives.

Cyclooxygenase-2 enzyme inhibitors: place in therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) play a major role in the management of inflammation and pain caused by arthritis. A new class of NSAIDs that selectively inhibit the cyclooxygenase-2 (COX-2) enzyme has been developed. The first COX-2 inhibitors, celecoxib and rofecoxib, are said to provide therapeutic benefit with less toxicity than traditional NSAIDs. A third COX-2-selective inhibitor, meloxicam, has recently been introduced. COX-2 inhibitors and traditional NSAIDs do not appear to differ significantly in their effectiveness in alleviating pain or inflammation. They have similar gastrointestinal side effects, including abdominal pain, dyspepsia and diarrhea. However, short-term studies show fewer gastrointestinal ulcers in patients treated with COX-2 inhibitors compared with traditional NSAIDs.

Vinorelbine in advanced non-small cell lung cancer. A pharmacoeconomic review.

UNLABELLED: Vinorelbine is a semisynthetic vinca alkaloid that is effective against advanced non-small cell lung cancer (NSCLC). Myelosuppression is the primary dose-limiting toxicity; vinorelbine is otherwise relatively well tolerated. Two studies assessed the cost effectiveness of vinorelbine with or without cisplatin based primarily on data from a phase III comparison with vindesine plus cisplatin. Survival and cost data from this study were supplemented with those from other sources. One model simulated total management costs for the 4986 patients diagnosed with stage IV NSCLC in Canada in 1992. The other applied US cost data to the outcomes from the phase III trial. Using vinorelbine monotherapy or vinorelbine plus cisplatin produced a survival benefit and net cost savings compared with best supportive care according to the Canadian model (and preliminary data from a third analysis, conducted in the US). In the Canadian analysis, incremental cost effectiveness for inpatient or outpatient vinorelbine plus cisplatin ranged from 7450 Canadian dollars ($Can) to $Can30,770 (1993 values) per year of life saved (YLS) compared with outpatient cisplatin plus either etoposide or vinblastine. Cost-effectiveness ratios for vinorelbine plus cisplatin in the US analysis (1994 values) were $US18,000 (vs cisplatin plus etoposide) and $US15,500 (vs cisplatin plus vindesine) per YLS [all inpatient administration]. Detailed pharmacoeconomic comparisons with other current standard regimens (e.g. paclitaxel plus either cisplatin or carboplatin) are not available. Sensitivity analyses suggest that the cost effectiveness of vinorelbine-based therapy is robust to changes in assumptions regarding efficacy and the cost of managing toxicity. Limitations of the available pharmacoeconomic data include the retrospective nature of the analyses, inclusion of data from sources other than the main phase III trial (e.g. those for best supportive care and some chemotherapy regimens), and exclusion of some costs for hospitalisation and/or management of toxicity. CONCLUSIONS: Although some limitations apply, the available data suggest that vinorelbine alone or in combination with cisplatin is cost saving compared with best supportive care for NSCLC, and that vinorelbine plus cisplatin is cost effective compared with some other combination regimens. The pharmacoeconomic placing of vinorelbine in relation to a number of other currently recommended first-line treatments for NSCLC has yet to be resolved, and data from ongoing multicentre phase III trials are awaited with interest. In the meantime, vinorelbine-based chemotherapy appears to be a suitable choice for first-line treatment of advanced NSCLC from both clinical and pharmacoeconomic perspectives.

Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery.

UNLABELLED: Cardiopulmonary bypass (CPB) is associated with defective haemostasis which results in bleeding and the requirement for allogenic blood product transfusions in many patients undergoing open heart surgery (OHS) and/or coronary artery bypass graft surgery (CABG) with CPB. Conservation of blood has become a priority during surgery because of shortages of donor blood, the risks associated with the use of allogenic blood products and the costs of these products. Aprotinin is a serine protease inhibitor isolated from bovine lung tissue which acts in a number of interrelated ways to provide an antifibrinolytic effect, inhibit contact activation, reduce platelet dysfunction and attenuate the inflammatory response to CPB. It is used to reduce blood loss and transfusion requirements in patients with a risk of haemorrhage and has clear advantages over placebo or no treatment. High dose aprotinin significantly reduces postoperative blood loss compared with aminocaproic acid and desmopressin, and decreases transfusion requirements compared with desmopressin. Results are less consistent with tranexamic acid: high dose aprotinin either reduces blood loss significantly more than, or to an equivalent level to, tranexamic acid. A variety of other lower aprotinin dosage regimens consistently result in similar reductions in blood loss to aminocaproic acid or tranexamic acid. Data from clinical trials indicate that aprotinin is generally well tolerated, and the adverse events seen are those expected in patients undergoing OHS and/or CABG with CPB. Hypersensitivity reactions occur in <0.1 to 0.6% of patients receiving aprotinin for the first time. The results of original reports indicating that aprotinin therapy may increase myocardial infarction rates or mortality have not been supported by more recent studies specifically designed to investigate this outcome. However, a tendency to early vein graft occlusion with aprotinin has been shown and care with anticoagulation and vessel grafts is required. No comparative tolerability data between aprotinin and the lysine analogues, aminocaproic acid and tranexamic acid, are available. CONCLUSION: Comparative tolerability and cost-effectiveness data for aprotinin and the lysine analogues are required to more fully assess their individual roles in reducing blood loss and transfusion requirements in patients undergoing CPB during OHS and/or CABG. However, clinical evidence to date supports the use of aprotinin over its competitors in patients at high risk of haemorrhage, in those for whom transfusion is unavailable or in patients who refuse allogenic transfusions.

Assessment of intubating conditions in adults after induction with propofol and varying doses of remifentanil.

We have assessed intubating conditions in three groups of 60 ASA I or II patients after induction of anaesthesia with propofol 2 mg kg-1 and remifentanil 0.5, 1.0 or 2.0 micrograms kg-1. Tracheal intubation was graded according to ease of laryn-goscopy, position of the vocal cords, coughing, jaw relaxation and movement of the limbs. Intubation was successful in 80%, 90% and 100% of patients after remifentanil 0.5, 1.0 or 2.0 micrograms kg-1, respectively. Overall intubating conditions were regarded as acceptable in 20%, 50% and 80% of patients, respectively. All three groups had a decrease in arterial pressure after induction but there was no difference between groups. The decrease in arterial pressure was not regarded as clinically significant. Intubating conditions were best after induction with remifentanil 2 micrograms kg and propofol 2 mg kg-1.

Ticlopidine. A review of its pharmacology, clinical efficacy and tolerability in the prevention of cerebral ischaemia and stroke.

Ticlopidine is a thienopyridine derivative which reduces the risk of reversible ischaemia and stroke in patients who have previously experienced a cerebral ischaemic episode. In comparison with aspirin, ticlopidine produced a significant reduction in the risk of stroke in a multicentre clinical trial involving more than 3000 patients with previous transient or persistent minor ischaemia, and was superior to placebo for the prevention of stroke recurrence in more than 1000 patients who had experienced a major thrombotic stroke. The cost-utility ratio for ticlopidine in comparison with aspirin was estimated to be $US31 200 to 55,000 per quality-adjusted life-year gained. Diarrhoea is the most common adverse event in ticlopidine recipients (20 to 22% incidence versus about 10% with placebo), although skin rash, nausea, dyspepsia, bleeding events, abnormal liver function and haematological disturbances were also observed in clinical trials. Severe neutropenia is the most serious event: this developed in 0.85% of patients receiving ticlopidine in 2 large clinical studies (n = 4098) but resolved after treatment withdrawal. Fatal neutropenia, although rare, has been reported in some patients receiving ticlopidine. Thus, ticlopidine is effective in reducing the risk of recurrent cerebral ischaemia and stroke. It appears to provide a gain over aspirin for the prevention of stroke after reversible ischaemia, particularly during the first year of treatment (when the risk of stroke is greatest), although further data on its absolute relative benefit would be useful. The extent to which ticlopidine is prescribed will probably depend on individual clinicians' perception of its risk/benefit and cost-effectiveness profiles. Ticlopidine is likely to be particularly useful for stroke prophylaxis in patients who do not tolerate aspirin or who have an ischaemic episode during aspirin treatment, and for the prevention of stroke recurrence in patients who have previously experienced a major stroke.

General practice fundholding: observations on prescribing patterns and costs using the defined daily dose method.

OBJECTIVE: To compare prescribing patterns between a group of fundholding practices and a group of non-fundholding practices in north east Scotland using a method which provides more accurate statements about volumes prescribed than standard NHS statistics. DESIGN: The pharmacy practice division of the National Health Service in Scotland provided data for selected British National Formulary sections over two years. Each prescription issued was converted using the World Health Organisation "defined daily dose" mechanism. SETTING: Six fundholding groups (nine practices) in Grampian and Tayside regions and six non-fundholding practices in Grampian. RESULTS: During the past two years both fundholding and control practices reduced the volume of their prescribing for the classes of drug analysed. The unit costs of drugs in some classes, however, rose substantially, contributing to higher costs per patient. The unit costs rose more in the control practices (24%) than in the fundholding practices (11% in Tayside, 16% in Grampian). CONCLUSION: The use of defined daily doses helped identify cost and volume trends in specific areas of prescribing in fundholding and control practices. The basis on which funds are set needs improving, and defined daily doses may prove useful for setting volume targets within drug classes for all practices, whether fundholding or not.